Latently infected, resting memory CD4 T cells represent a major obstacle to eradication of HIV within infected individuals. Current knowledge of the interactions between viral and cellular elements that work to maintain HIV latency is limited. A major obstacle to advancement in this research area is the difficulty associated with studying such latently infected T cells, which exist at extremely low frequencies in the blood of infected individuals. To circumvent this problem, Project 2 proposes to use biologically relevant primary T cell systems to evaluate HDAC inhibitors, and other selected small molecule compounds, for their ability to impact HIV latency. In Aim 1, an established, well-characterized in vitro primary CD4 cell model of latent HIV infection will be used to test promising treatment candidates, identified in Project 1. Detected effects will be confirmed and characterized further, using ex vivo cultures of CD4 lymphocytes from HAART-suppressed HIV-infected patients. In Aim 2, the efficacy of selected treatments for the SIV/rhesus model will be tested ex vivo using CD4 cells isolated from the peripheral blood and lymph nodes of SIV-infected, ART-suppressed macaques, obtained from Project 1. In Aim 3, we will work in collaboration with Project 3 to identify molecular mechanisms involved in the activation of latent HIV infection from resting CD4 cells. Within the cooperative program, the overall aim of Project 2 is the development and application of in vitro cell culture systems to identify treatments that have a high probability for success in activating retroviral latency when applied in vivo. One major goal is to contribute towards the validation of the SIV/macaque model of retroviral latency as a surrogate for HIV latency. The longrange objective of this project is the identification of new small molecule treatments that are effective in selectively activating latent HIV provirus, for the purpose of depleting the latently infected cell reservoir.